Proteolytic cleavages of the amyloid precursor protein (APP) generate beta-amyloid peptides (A?). Although beta-amyloid pathology is the hallmark of Alzheimer's disease (AD), synaptic dysfunction is believed to play a primary role in AD pathogenesis. Since A? is produced as part of APP processing, we reasoned that understanding the mechanisms of APP and its processing products in synaptic function, and investigating the effects of A? in the context of APP are of crucial importance. Whereas various neuronal and synaptic activities of APP have been proposed, their physiological relevance remains largely unestablished. To this end, we generated mice deficient in APP and reported that APP plays a functional role in hippocampal synaptic plasticity and learning and memory. We recently created a strain of APP conditional knockout mice. Analysis of these animals demonstrates an essential role for the APP family of proteins in neuronal survival and synaptic structure and function. Intriguingly, APP-mediated synaptogenic activity requires its expression in both pre- and postsynaptic compartments, supporting a functional interaction of APP across synapse. Our proposal is aimed at testing this trans-synaptic APP interaction model, deciphering the activities of APP processing products, including A?, in APP-mediated synaptic property, and identifying the APP downstream targets using a combination of state-of-the-art in vitro technologies and physiological and disease-relevant mouse models. In particular, we are equipped with the novel APP conditional knockout mice and humanized APP/A? knock-in mice and are uniquely positioned to address these fundamental questions concerning the pathophysiology of APP and A? in central synapses. PUBLIC HEALTH RELEVANCE: APP plays a central role in AD pathogenesis; synaptic dysfunction is widely accepted as the primary cause of AD. Although A? has been the focus of AD research, it is often overlooked that it is generated as part of normal APP processing. As such, physiology is intimately linked with pathogenesis, and deregulation of A? is expected to simultaneously affect other APP metabolites and APP-mediated pathways. Our recent finding that APP may function as a synaptic adhesion protein and that APP family of proteins is essential for the maintenance of adult neurons open up a new and exciting direction for achieving a fundamental understanding of the pathophysiology of APP. Accordingly, determining the molecular and cellular mechanisms of APP in neuronal and synaptic regulation and investigating the effect of A? in the context of APP using physiological and disease relevant mouse model systems as proposed represent a novel and much needed area of AD research. Our studies will provide a comprehensive understanding of the role of APP in synaptic regulation and reveal new pathogenic insights into Alzheimer's disease.